Prenylation consists of the addition of an isoprenoid group to a cysteine residue located near the carboxyl terminal of a protein. This enzymatic posttranslational modification is important for the maturation and processing of proteins. Both processes are necessary to mediate protein-protein and membrane-protein associations, in addition to regulating the localisation and function of proteins. The severe phenotype of animals deficient in enzymes involved in both prenylation and maturation highlights the significance of these processes. Moreover, alterations in the genes coding for isoprenylated proteins or enzymes that are involved in both prenylation and maturation processes have been found to be the basis of severe human diseases, such as cancer, neurodegenerative disorders, retinitis pigmentosa, and premature ageing syndromes. Recent studies on isoprenylation and postprenylation processing in pathological conditions have unveiled surprising aspects of these modifications and their roles in different cellular pathways. The identification of these enzymes as therapeutic targets has led researchers to validate their effects in vitro and in vivo as antitumour or antiageing agents.
Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single arm clinical trials have administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study has assessed whether treatments influence patient survival.
Identification of the molecular mechanisms leading to premature aging in children affected by Hutchinson Gilford progeria syndrome (HGPS) (OMIM #176670) has allowed clinicians to test targeted repurposed drugs. However, up to now, the lack of appropriate in vitro cellular models has precluded wider assays of chemical entities using high throughput screening (HTS).
HGPS is an extremely rare genetic disease (Merideth et al., 2008, N Engl J Med, Vol. 358: 592-604) due to a single-base substitution in exon 11 of the LMNA gene (De Sandre-Giovannoli et al., 2003, Science, Vol. 300: 2055; Eriksson et al., 2003, Nature, Vol. 423: 293-298) (c.1824C>T, NCBI Reference Sequence: 170707.3). This leads to the activation of a cryptic splicing donor site yielding to the deletion of 50 amino acids in prelamin A and the production of a toxic form of the prelamin A protein called progerin (Navarro et al., 2004, Hum Mol Genet, Vol. 13: 2493-2503).
Because the deleted sequence is required to its posttranslational maturation, this mutant protein accumulates at the nuclear membrane, and this is the main mechanism leading to segmental premature and accelerated aging in patients. While the disorganization of the nuclear shape is easily observed in HGPS cells, a set of well characterized cellular dysfunctions is associated, including premature senescence as well as defects in DNA repair, cell proliferation and differentiation.
Since the discovery of the molecular mechanisms leading to HGPS, three different drugs have been repurposed for their ability to target the prenylation process, namely the HMG-CoA reductase (GCR) inhibitor pravastatin associated to the amino-bisphosphonate zoledronate, and the farnesyl transferase inhibitor (FTI) lonafarnib (Varela et al., 2008, Nat Med, Vol. 14: 767-772; Yang et al., 2005, Proc Natl Acad Sci USA, Vol. 102: 10291-10296; Yang et al., 2010, Journal of lipid research, Vol. 51: 400-405). Over the past 10 years, several experimental studies have indeed demonstrated the relevance of these pharmacological approaches showing that inhibition of the prelamin A prenylation process correlated with an improvement of the nuclear shape and other cellular defects related to HGPS. Altogether these studies have triggered the elaboration of three clinical trials (Capell et al., 2005, Proc Natl Acad Sci USA, Vol. 102: 12879-12884; Capell et al., 2008, Proc Natl Acad Sci USA, Vol. 105: 15902-15907; G1 and Glover, 2005, Human Mol Genet, Vol. 14: 2959-2969; Varela et al., 2008, Nat Med, Vol. 14: 767-772; Young et al., 2013, Sci Transl Med Vol. 5: 171ps173) that revealed some partial improvements of patients' clinical phenotypes, making it essential to discover new potential molecules (Gordon et al., 2012, Proc Natl Acad Sci USA, Vol. 109: 16666-16671).
Thanks to their pluripotency and self-renewal properties, embryonic stem cells and (ES) induced pluripotent stem (iPS) cells offer a unique way to produce an unlimited and homogeneous biological resource for testing chemical compounds in vitro, in a HTS setting (Desbordes and Studer, 2013, Nat Protoc, Vol. 8: 111-130; Lee et al., 2012, Nat Biotechnol, Vol. 30: 1244-1248). Since 2011, several groups have demonstrated the capacity of iPS cell lines to recapitulate some aspects of HGPS after differentiation into vascular smooth muscle cells (VSMCs) and mesenchymal stem cells (MSCs) (Liu et al., 2011, Nature, Vol. 472: 221-225; Nissan et al., 2012, Cell Rep, Vol. 2: 1-2; Zhang et al., 2011, Cell Stem Cell, Vol. 8: 31-45). More recently it has been shown that those cells could be used to evaluate, in vitro, the functional effects of the drugs that are currently used in HGPS patients on typical cellular and molecular defects, such as nuclear shape architecture, progerin expression and their premature differentiation along the osteoblastic lineage (Blondel et al., 2014, Stem cells Transl Med, Vol. 3: 510-519).
There is a need in the art for the availability of further compounds useful in the prevention or in the treatment of diseases or disorders wherein an inhibition of protein prenylation is required.